tbuckley/cabot-search huggingface dataset:
DDEL-05. PHARMACOKINETICS AND CNS DISTRIBUTION OF A NOVEL ATM INHIBITOR, WSD0628, FOR THE TREATMENT OF BRAIN TUMORS
Authors: Sneha Rathi, Ju-Hee Oh, Jann Sarkaria, William F Elmquist
Journal: Neuro-Oncology (2022)

Abstract The treatment of brain tumors using chemo- and radio-sensitizers may be limited by a lack of effective drug delivery. Radiation and some cytotoxic therapies induce DNA damage, and DNA damage response (DDR) pathways modulate resistance to effective chemo-radiation therapy. Inhibiting DDR pathways by targeting ATM leads to sensitization and enhances cytotoxicity. The purpose of this study is to determine the key pre-clinical pharmacokinetic parameters and mechanisms that influence the CNS delivery of WSD0628, a novel ATM inhibitor. Pharmacokinetics and CNS distribution studies were conducted in FVB wild-type mice following intravenous (IV) and oral (PO) dosing (5 mg/kg). Plasma, brain, and spinal cord samples were harvested after dosing and drug concentrations were measured using LC-MS/MS. The free fraction of WSD0628 was measured in plasma, brain, and spinal cord using rapid equilibrium dialysis. Our results indicate that WSD0628 has a half-life of 4.11 hrs and a high oral bioavailability (0.95). The brain partition coefficient (AUCbrain/AUCplasma, i.e., Kp, brain) is 0.05 and 0.11 after IV and PO dosing, respectively. The free fraction in plasma is 2.01 ± 0.02 % and in brain it is 1.22 ± 0.40 %. The unbound brain partition coefficient (Kpuu brain) is 0.03 and 0.06 after IV and PO dosing, respectively. The differential binding to plasma and brain tissues results in a relatively low Kpuu, a key parameter describing brain penetrability. These data show that WSD0628, a highly potent inhibitor of ATM, reached sufficient concentrations in brain after a single dose of 5 mg/kg to engage ATM over the desired time frame and elicit a response after DNA damage by chemo-radiotherapy. WSD0628 shows promising potential and further evaluations are underway to determine if efflux transporters at the BBB limit its brain distribution.
NCMP-21. PEMBROLIZUMAB-ASSOCIATED MYOSITIS, MYASTHENIC CRISIS, AND MYOCARDITIS IN A PATIENT WITH METASTATIC UROTHELIAL CARCINOMA
Authors: Laura Hein, Anisha Narayan, Franco Lia, Pedro Barata, Christopher Trevino
Journal: Neuro-Oncology (2022)

Abstract Although immune checkpoint inhibitors (ICIs) have improved systemic cancer care, in rare cases, patients develop neuromuscular immune related adverse events (irAEs), which carry high morbidity and mortality. This case study describes an 85-year-old male who developed the triad of myositis, myasthenic crisis, and myocarditis in association with ICI treatment for metastatic urothelial carcinoma (T3N0M1). The patient developed progressive weakness and gait impairment five weeks after initiating treatment with pembrolizumab. Later, he developed reduced ambulation, fatigue, shortness of breath, and orthopnea with concomitant ECG changes. Clinical exam demonstrated dysphagia, ptosis, proximal muscle weakness, fatigable weakness, and areflexia, ultimately resulting in respiratory failure, intubation, and inability to stand. Lab workup revealed elevated creatinine kinase, myoglobin, lactate dehydrogenase, and aldolase, but was notably negative for acetylcholine receptor and muscle specific kinase antibodies. Labs, clinical timeline, and clinical features supported his diagnoses. Interestingly, the cytokine panel demonstrated a high-normal soluble IL-2 receptor alpha which supports autoimmune pathology and elevated IL-10. The patient was treated with pyridostigmine, prednisone, and plasma exchange (PLEX) for 10 exchanges. EMG 10 days into treatment supported evidence of inflammatory myositis. After methylprednisone and PLEX treatment, the patient’s symptoms improved to ambulation with a walker and occasional BiPap support. His metastatic disease remained stable for several weeks while holding pembrolizumab due to toxicity. This case illustrates how early intervention and aggressive treatment for neuromuscular ICI-induced triad can stabilize patients and improve neurologic recovery. Due to the high morbidity and mortality for these irAEs, the authors support increased clinical scrutiny when evaluating these rare conditions and consideration of investigating the acute inflammatory processes. With improved pathophysiologic understanding of these rare conditions, the community can improve outcomes and refine treatments.
RADT-35. A PROSPECTIVE REGISTRY STUDY OF 68GA-DOTATATE PET INCORPORATION INTO TREATMENT PLANNING OF INTRACRANIAL MENINGIOMAS
Authors: Haley Perlow, Rahul Prasad, Michael Siedow, Yevgeniya Gokun, Jennifer Matsui, Dukagjin Blakaj, Sasha Beyer, Evan Thomas, Raju Raval, Arnab Chakravarti, Daniel Prevedello, Douglas Hardesty, James Elder, Joshua Palmer
Journal: Neuro-Oncology (2022)

Abstract Introduction The current standard for meningioma radiation planning involves MRI-based image guidance. SSTR ligands such as 68Ga-DOTATATE are being explored for meningioma radiotherapy treatment planning due to universal expression of somatostatin receptor 1/2 in meningioma tissue. We hypothesize that 68Ga-DOTATATE PET utilization can reduce the risk of local failure (LF) through precise radiation planning and may also suggest that patients who have local PET avidity after a perceived GTR may be poor observation candidates. METHODS A single institution prospective registry study was created and included intracranial meningioma patients who received a 68Ga-DOTATATE PET scan to assist with radiation oncologist decision-making. These were ordered for all meningioma patients as a departmental standard. Patients who received a PET scan from 1/1/2018-2/25/2022 were eligible for inclusion. RESULTS 60 patients were treated in this prospective registry. 22%, 72%, and 7% were World Health Organization (WHO) high, intermediate, and low-risk, respectively. After completing their PET scan, 48, 11, and 1 patient(s) proceeded with RT, observation, or redo craniotomy. The median follow up was 16 months (IQR 8.3-23.1). 3 patients (5%) experienced LF between 9.2-28.5 months after diagnosis. 2 patients with LF had PET-avid disease in their post-operative cavity and elected for observation prior to recurrence, and 1 high-risk patient with multifocal disease experienced LF 2 years after a second radiation course and multiple previous recurrences. LF rates after radiation were 0%, 0%, and 8% in the low, intermediate, and high-risk cohorts, respectively. There were no Grade 3 or higher toxicities attributed to PET-guided radiation. CONCLUSION This is the largest known population of intracranial meningioma patients followed by physicians who utilized 68Ga-DOTATATE PET guided therapy. Only 1 patient experienced LF after receiving PET-guided radiation therapy, likely due to a radioresistant histology. Incorporating 68Ga-DOTATATE PET into future trials may assist with clinician decision-making and improve patient outcomes.
CSIG-16. EXPLOITING A NEGATIVE FEEDBACK LOOP LINKING S6 KINASES AND AXL TO REDUCE PYRIMIDINE BIOSYNTHESIS IN PTEN-DEFICIENT GLIOBLASTOMA
Authors: Catherine Behrmann, Pranjal Sarma, Kelli Ennis, Collin Wetzel, Nicholas Clark, Subrahmanya Vallabhapurapu, James Reigle, Jarek Meller, Xiaoyang Qi, Mario Medvedovic, Soma Sengupta, Biplab Dasgupta, David Plas
Journal: Neuro-Oncology (2022)

Abstract PTEN inactivation triggers oncodependent signal transduction through the PI3K/Akt signal transduction pathway in glioblastoma (GBM). Targeting the PI3K/Akt pathway to counteract PTEN loss in GBM has been impeded by negative feedback signal transduction networks mediated by the downstream protein kinases S6K1 and S6K2. Here, we show that the receptor tyrosine kinase AXL is a major target of that S6K feedback signaling and that combined inactivation of just S6K1 and AXL is an effective therapeutic strategy for treatment of PTEN-deficient GBM. Chemical-genetic interaction studies in gliomasphere and GBM cell lines revealed critical and independent roles for S6K1 and S6K2 in mediating GBM growth in PTEN-deficient cells. Interestingly, S6K2 exerted a dual role in signal transduction: it sustained GBM growth while also exerting negative feedback control on the upstream receptor tyrosine kinase AXL. Genetic inactivation of S6K2 sensitized PTEN-deficient GBMs to AXL inhibition, indicating that derepressed AXL is required for compensatory signaling upon targeting of the PI3K/Akt pathway. Combining the AXL inhibitor BMS-777607 with S6K1 inhibitor LY-2584702 also prevented compensatory AXL signaling and triggered cytotoxic responses selectively in the PTEN-deficient condition. Importantly, combination inhibition of AXL and S6K1 reduced pyrimidine biosynthesis, a known vulnerability of PTEN-deficient GBMs. The oral inhibitors of S6K1 and AXL were found to be brain-penetrant and effective in reducing GBM growth in several mouse models. These results establish that targeting of AXL can circumvent S6 Kinase dependent feedback to reduce pyrimidine biosynthesis and trigger cytotoxic responses in PTEN-deficient GBMs.
NIMG-45. DISTINGUISHING PROGRESSION FROM PSEUDOPROGRESSION IN GLIOBLASTOMA: COMBINED USE OF 18F-FLUCICLOVINE PET AND MULTI-PARAMETRIC MRI
Authors: Ali Nabavizadeh, Stephen Bagley, Jeffrey B Ware, Robert K Doot, Anthony Young, Satyam Ghodasara, Chao Zhao, Hannah Anderson, Erin Schubert, Erica L Carpenter, Jacob Till, Fraser Henderson, Austin R Pantel, Isaac Chen, John Y K Lee, Nduka Amankulor, Donald O'Rourke, Arati Desai, MacLean Nasrallah, Steven Brem
Journal: Neuro-Oncology (2022)

Abstract PURPOSE Differentiation of tumor progression (TP) from pseudoprogression (PsP) is a major unmet need in post-treatment glioblastoma (GBM). 18F-Fluciclovine is a synthetic amino acid PET radiotracer with higher uptake in tumor tissue vs. areas of treatment-related change. We investigated the value of 18F-Fluciclovine PET for differentiating PsP from TP independent from and in combination with multi-parametric MRI. METHODS We prospectively enrolled 30 patients with GBM with a new or enlarging contrast-enhancing lesion on MRI after chemoradiotherapy who were planned for surgical resection of the lesion. Patients underwent pre-operative 18F-Fluciclovine PET and multi-parametric MRI. Following surgery, the relative percentages of viable tumor and therapy-related changes observed in histopathology were quantified. Patients were categorized as TP if viable tumor represented ≥ 50% of the specimen, mixed TP if &amp;lt; 50% and &amp;gt; 10%, and PsP if ≤ 10%. RESULTS 18 patients had TP, 4 had mixed TP, and 8 PsP. Patients with TP/mixed TP had a significantly higher 40-50 minutes SUVmax (6.64 + 1.88 vs 4.11± 1.52, p=0.009) and an SUVmax cut-off of 4.66 provided 90% sensitivity and 83% specificity for differentiation of TP/mixed TP from PsP (AUC=0.856). A maximum cerebral blood volume (CBVmax) cut-off of 3.67 provided 90% sensitivity and 71% specificity for differentiation of TP/mixed TP from PsP (AUC=0.779). Combining a 40-50 minutes SUVmax cut-off of 4.662 and a relative CBVmax cut-off of 3.67 provided 100% sensitivity and 80% specificity for differentiating TP/mixed TP from PsP (AUC=0.95). The time activity curve patterns and time to peaks were not different between the groups. Normalization of PET parameters to normal brain parenchyma were not helpful to differentiate the groups due to variability in radiotracer uptake in normal brain between subjects. CONCLUSION 18F-Fluciclovine PET uptake can accurately differentiate PsP from TP in GBM patients, with even more accurate differentiation achieved when combined with MRI.
NCMP-05. RARE CASE OF INTRAMEDULLARY SPINAL CORD METASTASIS AND CANCER-RELATED STROKE SECONDARY TO NASOPHARYNGEAL CARCINOMA
Authors: Anisah Hayaminnah Alonto, Mark Willy Mondia, Cyril Jonas Planilla, Marvin Jonne Mendoza, Sheen Urquiza, Rich Ericson King, Marjorie Anne Bagnas
Journal: Neuro-Oncology (2022)

Abstract INTRODUCTION Central nervous system (CNS) metastasis from nasopharyngeal carcinoma (NPC) is rare and presents with high morbidity and mortality. As a rare entity, a few patients with CNS metastasis from NPC have been reported, and no studies were available on treatment and prognosis. Based on our clinical experience, early diagnosis with incorporation of a clear palliative plan is imperative in providing holistic care for patients with locally-invasive and metastatic nasopharyngeal carcinoma. CASE REPORT Our study reports a case of a 48-year-old Filipino male with known NPC Stage IVB who developed acute symptoms of constipation, urinary retention, and bilateral lower limb weakness and numbness. Magnetic resonance imaging (MRI) showed intramedullary lesions in multiple segments of the spinal cord. Steroid and radiotherapy of the spine were initiated with noted transient improvement of the motor strength. Subsequently, he developed cancer-related stroke. The patient progressively deteriorated despite best medical care. To our knowledge, this is the fourth case of intramedullary spinal cord metastasis from NPC reported worldwide but the first one in the Philippines.
CTIM-15. RESULTS OF A PHASE IB TRIAL OF RECOMBINANT POLIO:RHINOVIRUS IMMUNOTHERAPY FOR RECURRENT PEDIATRIC HIGH GRADE GLIOMA
Authors: Eric Thompson, Daniel Landi, Michael Brown, Henry S Friedman, Roger McLendon, Dani Bolognesi, Kristin Schroeder, Oren Becher, Allan Friedman, Ashley Walter, Stevie Threatt, Denise Jaggers, Annick Desjardins, Matthias Gromeier, Darell Bigner, David Ashley
Journal: Neuro-Oncology (2022)

Abstract BACKGROUND Outcomes of recurrent pediatric high grade glioma (pHHG) are poor with a median overall survival (OS) of &amp;lt; 6 months. Viral immunotherapy such as the polio:rhinovirus chimera, PVSRIPO, is a novel treatment approach for recurrent pHHG. PVSRIPO is genetically engineered to prevent neurovirulence. In adults with recurrent glioblastoma treated with PVSRIPO, 21% survived &amp;gt; 36 months. The poliovirus receptor, CD155, is ubiquitously expressed in malignant pediatric brain tumors including pHHG. METHODS The primary objective of this Phase 1b clinical trial was to evaluate the safety and feasibility of PVSRIPO for recurrent pHGG. PVSRIPO was given at a single dose, 5x107 50% tissue-culture infectious dose (TCID50) administered by convection enhanced delivery (CED) to children with biopsy-confirmed recurrent pHHG between ≥ 1 and ≤ 5.5 in diameter. 3 mL of PVSRIPO was delivered at 0.5 mL/hr via a single catheter. RESULTS Eight patients were treated with PVSRIPO including 5 males and 3 females with a median age of 16.5 (range 9-19). Six patients had recurrent glioblastoma, 2 had recurrent anaplastic astrocytoma. The median number of previous recurrences prior to enrollment was 3.5 (range 1-5). Four patients received bevacizumab on-study for treatment-related peritumoral inflammation/edema. Six of 8 patients experienced 26 treatment related adverse events (AEs) possibly, probably, or definitely related to protocol treatment. There were no Grade 4 or 5 AEs. There were 3 Grade 3 AEs: 2 headaches and 1 seizure. There were no AEs related to biopsy or CED catheter insertion/removal. Median OS was 4.13 months (range 1.23-NA). One patient is currently alive at &amp;gt; 21 months. Monocyte and T cell inflammatory phenotypes and total CD4+ T cells were increased in peripheral blood after treatment. CONCLUSIONS CED of PVSPRIO is both safe and feasible for the treatment of recurrent pHHG. Histologic correlative results will also be presented.
DDDR-04. CA-4948 IN COMBINATION WITH BRAF/MEK INHIBITION IN MELANOMA BRAIN METASTASES
Authors: Bently Doonan, Christina Von Roemeling, Vincent Archibald, Kelena Klippel, Tyler Elliott, Erica Matich, Lan Hoang-Minh, Duane Mitchell
Journal: Neuro-Oncology (2022)

Abstract Melanoma brain metastases (MBM) remain a primary driver of melanoma morbidity and mortality. It is estimated that as many as 60% of all metastatic melanoma patients will develop MBM during the course of their disease. Once found, dual checkpoint inhibitor therapy or BRAF/MEK inhibition in BRAF mutated cancers, are the best options currently available. Even with these treatments, the response to therapy is less than what is seen with disease outside the. In BRAF mutated cancers, which constitute 50% of all patients, initial response to targeted therapy is rapid but resistance to therapy develops 3 months sooner than resistance outside of the brain. Novel strategies to prevent onset of resistance or to work in concert with BRAF/MEK inhibition are needed for this treatment population. The exact mechanism of resistance to targeted therapy in MBM is not known, but mutations in EphA2, PI3K, pAKT, and re-activation of MAPK signaling through secondary mechanisms have all been identified as drivers of resistance. One pathway of MAPK reactivation is through activation of phospho-ERK (eIF2alpha kinase) which also activates the JNK pathway. Our group has previously shown that MBM express high levels of the inflammatory transcription factor IRAK-4, the terminal chaperone of the inflammatory myddosome downstream of TLR and IL1R signally. This increase in IRAK-4 results in constitutive activation of NF-KB, JNK, and MAPK. We have additionally shown the novel oral IRAK-4 inhibitor CA-4948 can reach therapeutically relevant concentrations past the blood brain barrier in both tumor-bearing and naïve mice. We additionally show CA-4948 inhibits MAPK expression in melanoma and suppresses the escape pathways pERK and JNK signaling which can contribute to the prevention of resistance to targeted therapy. This study supports further investigation into the combination potential of CA-4948 with BRAF/MEK inhibitors as triplet therapy to delay intracranial resistance.
NCOG-45. DIFFERENTIAL AND DOSE-DEPENDENT EFFECTS OF CRANIAL IRRADIATION ON BRAIN STRUCTURES AND NEUROPSYCHOLOGICAL OUTCOMES IN CHILDREN WITH POSTERIOR FOSSA BRAIN TUMORS TREATED WITH DIFFERENT MODALITIES
Authors: Sofia Dhanani, Sharon O'Neil, Scarlet Cho, Brandon Shin, Marvin Nelson, Kenneth Wong, Arthur Olch, Jeffrey Tanedo, Oliver Biele, Jack Rodman, Natasha Lepore, Mary Nelson
Journal: Neuro-Oncology (2022)

Abstract BACKGROUND Studies investigating dose-dependent effects of cranial irradiation (CRT) in children with posterior fossa brain tumors are limited by examining combined effects of surgery, chemotherapy, and radiation. We aimed to determine alterations in brain volume and microstructure, and neuropsychological outcomes in children with posterior fossa tumors treated with surgery alone, surgery and chemotherapy, and surgery, chemotherapy, and CRT combined. We explored the relationship of radiation dose to the thalamus, putamen, and hippocampus to outcomes of intelligence, processing speed, executive functions, memory, and social/emotional functioning. METHODS Forty-seven children with treated posterior fossa tumors (17 with surgery; 11 with surgery and chemotherapy; 19 with surgery, chemotherapy, and CRT) underwent neuroimaging and neuropsychological assessment a mean of 4.8 years after treatment, along with 17 healthy sibling controls (n=64). The putamen, thalamus and hippocampus were manually segmented on MRI, and structural mean radiation doses were calculated. Differences in demographics and medical history were evaluated using χ2 and t-tests. Linear regression examined differences in neuropsychological performance, structural volumes, and diffusion indices. Pearson correlation explored relationships of structural radiation doses to diffusion indices and neuropsychological outcomes. RESULTS All patients scored lower on Block Design than controls (p=0.01), and the surgery and chemotherapy group scored the lowest. There was no significant difference in mean fractional anisotropy (FA) values in the thalamus, hippocampus and putamen between the three patient groups and controls. Hippocampal volume and mean radiation dose approached significant correlation (r= -0.49; p=0.07). Right putamen FA correlated with mean radiation dose (r=0.56; p=0.02). When controlling for age, thalamic volume was lowest in the irradiated group (p=0.02). CONCLUSIONS Treatment of pediatric posterior fossa brain tumors with surgery, chemotherapy, and CRT impacts thalamic volume and may have a dose-dependent effect on the microstructure of the putamen compared to treatment with surgery/chemotherapy.
CTIM-01. TITLE: PHASE 1B STUDY OF AVELUMAB AND WHOLE BRAIN RADIOTHERAPY (WBRT) IN PATIENTS WITH LEPTOMENINGEAL DISEASE (LMD): PRELIMINARY RESULTS
Authors: Yolanda Pina, Ann Chen, John A Arrington, Rob Macaulay, Nam Tran, James Liu, Sepideh Mokhtari, Jiannong Li, Vincent Law, Solmaz Sahebjam, Kamran Ahmed, Ben Creelan, Jhanelle Gray, Gerald Wallace, Brittany Evernden, Christine L Stewart, Nikhil Khushalani, Inna Smalley, Keiran Smalley, Michael Vogelbaum, Michael Yu, Peter Forsyth
Journal: Neuro-Oncology (2022)

Abstract BACKGROUND LMD from systemic cancer has a dismal prognosis with median survivals of 8-10 weeks. A phase 2 trial of PD-1 inhibitor monotherapy in LMD showed median overall survival (OS) of 3.6 months (Brastianos P et al., 2020). We determined the safety/efficacy of avelumab, a PD-L1 inhibitor with WBRT in patients with LMD (NCT0371768). This combination can treat the tumor directly and increase BBB permeability (Li, 2003; Nordal, 2005) allowing the increased egress of activated T cells into the meninges/CSF. METHODS Patients received concurrent avelumab 800 mg IV q2 weeks for ≤ 5 cycles (unless PD or unacceptable toxicity) with WBRT 3000 cGy in 10 fractions. Primary endpoints are safety/DLTs and OS at 3 months. Secondary endpoints are CSF T-cell/cytokine profiles (scRNAseq, phosophoproteomics etc.). RESULTS A total of 15 patients (7 breast, 7 lung &amp; 1 other) were enrolled (n = 13 F, ages 32-79). Pts receiving anti-PD-1/PD-1L/PD-L2/CD137,CTLA-4 therapy ≤ 6 months prior were excluded. Three of 15 patients had grade 3/4 AEs (diarrhea, lymphopenia, decreased WBC count in 3 patients). Seven patients (50%) were alive at 3 or 6 months. The estimated median follow up in 14 patients is 4.75 months (range, 0.92 – 30.05 months, 95% CI is 1.32 ~ 19.82). The median PFS is 3.75 months (95% CI = 0.85-15.16) and median OS is 6.89 months (95% CI = 1.18-14.7). CONCLUSIONS The combination of avelumab and WBRT is safe, well tolerated, and demonstrates encouraging activity in patients with LMD with an OS that is longer than other published series. Multiple platform interrogation of CSF (analysis underway) will determine mechanisms of LMD therapeutic/resistance effects.
TMIC-07. PYK2 SIGNALING IS UPREGULATED IN RECURRENT GLIOBLASTOMA TUMORS IN C57BL/6/GL261 GLIOMA IMPLANTATION MODEL
Authors: Jescelica Ortiz-Rivera
Journal: Neuro-Oncology (2022)

Abstract Glioblastoma (GBM) is the most aggressive type of brain cancer with no successful treatment available. Microglia makes up to 30% of total GBM tumor mass. Previously we demonstrated that microglia within the tumor stimulate glioma cell growth and invasion through the proline rich tyrosine kinase 2 (Pyk2). Tumor resection is the first line treatment for GBM. Our previous studies with use of mouse glioma implantation model indicate that microglia in a site of tumor resection undergo significant modulations in cytokines expression profile. We hypothesize that microglia activated by tumor resection induces Pyk2 signaling in glioma cell and promotes malignant properties of the tumor cells that fail to be eliminated by resection. Using C57BL/6/GL261 mouse glioma implantation model, we analyzed primary implanted tumors and re-grown tumor after surgical resection. Two weeks after glioma cells implantation, tumor resection was performed, and two weeks later regrown tumors were used for western blot analysis. Total Pyk2 and phosphorylated Pyk2[Y579/50] were analyzed. The study revealed that Pyk2 phosphorylation is upregulated in re-grown tumor compared to primary implanted tumor. Treatment with PF-562271 (Pyk2/FAK inhibitor, once/daily, 50mg/kg, orally) beginning the 2ndday after tumor resection, reduced Pyk2 phosphorylation in regrown tumors compared to animals that did not receive treatment with PF-562271. In conclusion we can state that tumor resection procedure induces the upregulation of Pyk2 phosphorylation in regrown tumors. This effect is eliminated with oral administration of PF-562271.